We propose to continue a line of research, enabled by an NIMH Merit Award, which has been testing hypotheses about neurobiologic manifestations of schizotaxia (the predisposition to schizophrenia) among schizophrenic patients and the nonpsychotic adult relatives of schizophrenic patients. Our work-showing that schizotaxia is associated with negative symptoms, neuropsychological dysfunction and structural brain abnormalities-converges with data from other centers to show that schizotaxia is a subtle brain disorder affecting about 20 to 50 percent of the nonpsychotic relatives of schizophrenic patients. The data collected during prior funding periods have allowed us to demonstrate a) neuropsychological deficits in schizophrenic patients and their relatives, b) gender differences in the expression of these deficits, c) stability of these deficits over time, d) structural brain abnormalities in patients and relatives, e) functional MRI abnormalities in patients and relatives, and f) how the psychometric features of neuropsychological tests make them useful for assessing phenotypes in genetic linkage studies of schizophrenia. We have decided to pursue three major aims in this continuation proposal that will help us better understand the neural substrates of schizotaxia and how they lead to schizophrenia. First, we will identify predictors of social dysfunction and psychopathology in adolescent children of schizophrenia patients. Second, we will better describe the neural substrate of schizophrenia prior to the onset of psychosis and lay the foundation for work that will examine if neurodegeneration occurs after illness onset. Third, we will establish the infrastructure required to monitor adolescents at risk for psychosis so that future proposals can select adolescents at risk for schizophrenia for prevention protocols. To accomplish these aims, we will assess 300 adolescent children of schizophrenic patients (ACSZ) and 50 normal controls with neuropsychological, psychosis proneness, psychosocial functioning, and family adversity measures. All controls and 150 randomly selected ACSZ will also be evaluated with magnetic resonance imaging. All 350 subjects will be monitored for adverse outcomes at six month intervals. Given the wide age range for the onset of schizophrenia, we plan to follow this sample for many years. Thus, we will also lay the foundation for future proposals that will monitor the incidence of psychosis in this sample through young adulthood. This will eventually allow us to assess 1)the predictive validity of schizotaxia measures and environmental adversity for subsequent psychosis and 2)longitudinal changes in neuro-psychological functioning and brain structure in subjects who do not become psychotic. Achievement of the second goal will help clarify which brain abnormalities in schizophrenic patients can be attributed to neurodevelop-mental events prior to onset and which are due to neurodegeneration after onset.